Changing the Way We Think About Endothelial Cell Insulin Sensitivity, Nitric Oxide, and the Pathophysiology of Type 2 Diabetes

Abstract

Recent changes in human lifestyles have led to a global epidemic of insulin-resistant type 2 diabetes (1). Type 2 diabetes is a multisystem disorder characterized by the disruption of insulin signaling pathways critical to the integration of tissue repair and nutrient homeostasis that results in loss of protection against a range of chronic disorders of human health including arterial atherosclerosis (2). As a result, type 2 diabetes is a major cause of myocardial infarction, stroke, and peripheral vascular disease affecting millions of individuals worldwide. Insulin resistance, characterized by an initial compensatory increase in insulin production, is a progressive disorder that can differentially affect organs, tissues, cells, and intracellular signaling pathways at different stages of the disease (3). It has recently emerged that in addition to its classical target tissues including liver, skeletal muscle, and adipose tissue, insulin resistance can occur in the endothelium where insulin has been shown to stimulate the release of the signaling radical nitric oxide (NO) (4). As a result, the endothelium, which was previously thought to be an inert lining of the blood vessel, is now established as a highly active organ that regulates a multitude of processes critical to vascular function (5). NO, a metabolite of L-arginine to L-citrulline conversion by endothelial NO synthase (eNOS), is released by the endothelium in response to cues such as shear stress and growth factors and has …